HIV-1 positive sera were tested for their ability to kill HIV-1 infected cells in the presence of complement. It was found that while fresh sera of humans didn't have antiviral activity, fresh sera of rodents showed a dose dependent viral-inactivating property against cell free HIV-1. The activity was destroyed by heating to 56 C, and apparently involves classical complement pathways. Elucidation of this mechanism may aid in understanding the lack of activity of human serum against HIV-1 and may prove useful in combined interventive strategies against HIV-1. We would like to test a panel of anti HIV-2 positive human sera for their ability to activate human complement by the classical pathway using HIV-2 infected cells. Activation will be assessed by flow cytometric detection of cell surface C3-deposition using C3-IgG conjugated to FITC. Analysis of complement mediated cytolysis of infected cells using defined antisera against recombinant HIV-1 env or core antigens suggested that the env, gp160/120 and gag, p24 acts as target antigens for antibody and complement mediated cytolysis. Complement alone reduced the spread of HIV-1 infection in CD4+ cells and the ability of HIV-1 & HIV-2 to form plaques in CD4- transfected HeLa cells. Cooperative effects of specific antibodies and complement were the most effective in inhibiting HIV-infection.